Boron neutron capture therapy (BNCT) is a binary treatment modality that can selectively irradiate tumor tissue. BNCT uses drugs containing a stable isotope of boron. {sup 10}B, to sensitize tumor cells to irradiation by low energy (thermal) neutrons. The interaction of the {sup 10}B with a thermal neutron (neutron capture) causes the {sup 10}B nucleus to split, releasing an alpha particle and a lithium nucleus. These products of the {sup 10}B(n, {alpha}){sup 7}Li reaction are very damaging to cells but have a combined path length in tissue of approximately 14 {mu}m, or roughly the diameter of one or two cells. Thus, most of the ionizing energy imparted to tissue is localized to {sup 10}B-loaded cells

Bergland, R.

Capala, J.

Joel, D.D.

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BNL-64 48 7 EARLY CLJNICAL EXPERIENCE OF BORON NEUTRON CAPTURE THERAPY FOR GLIOBLASTOMA MULTIFORME D.D. Joel', R. Bergland*, J. Capala'. M. Chadha', A.D. Chanana', J.A. Coderre', E. Elowitz', H.B. Liu' and D.N. Slatkin' Medical Department', Brookhaven National Laboratory, Upton, NY Departments of Neurosurgery' and Radiation Oncology, Beth Israel Medical Center, New York, NY RECE/ JUN24lpm .. O S T l  Boron neutron capture therapy (BNCT) is a binary treatment modality that can selectively irradiate tumor tissue. BNCT uses drugs containing a stable isotope of boron, I%, to sensitize tumor cells to irradiation by low energy (thermal) neutrons. The inr-adon'of the '08 with a thermal neutron (neutron capture) causes the ''% nucleus to split, releasing an alpha particle and a lithium nucleus. These products of the '@E%(n,cr)'Li reaction are very .damaging to cells but have a combined path length in tissue of approximately 14 pm, or roughly :he diameter of one )r two cells. Thus, most of the ionizing energy imparted to tissue is localized to '%-load& cells. Biodistribution of the Boron Carrier A Phase 1/11 clinical trial of BNCT for glioblastoma multiforme using the epithermal neutron beam at the Brookhaven Medical Research Reactor is underway. The boron compound tested in this initial trial is the amino acid analog p-boronophenylalanine (BPA). Prior to the initiation of Phase 1/11 clinical irradiations, the biodistribution of BPA was studied in patients with glioblastoma muitiforme scheduled for debulking surgery. The BPA was solubilized for intravenous infusion by complex formation with fructose (1). The administered dose of BPA was escalated from 130 mg/kg body weight to 250 mgikg body weight. All BPA-F infusions were 2 hours in duration. Figure 1 shows the boron concentrations in tumor and blood. Boron concentrations in the tumor samples are variable. Histologic examination of tumor sections adjacent to the samples used for boron analysis show areas of microscopic necrosis that vary from patient to patient and within multiple tumor samples from an individual patient. The boron analysis provides an average value for the entire sample. The tumor boron values shown in Figure 1 are mean values (k sd) which underestimate the amount of boron in highly cellular areas of tumor. The average boron concentration correlates with the degree of cellularity measured in histological sections, indicating that tumor accumulates approximately three times more boron that is present in the blood. Boron concentrations in the normal brain have been equal to or less than the boron concentrations observed in the blood in all patients. Boron cincentrations in scalp biopsies have been = 1.5 times higher than those o'lserved in blood. .. hese results are consistent with data from Japan using 170 mg BPAlkg i.: thermal neutron BNCT of malignant melanoma (2). Radiob ,logical Considerations. The m 1 . d  radiation field produced during BYCT comprises radiations with different linear energy transfer (LET) characteristics and different efficacies in biological systems. To express the total BNCT dose in a common unit, a ~ d  to compare BNCT doses with the effects of LaTRlBUTION OF THIS DOCUMENT IS U N L I M W  a i o  12 0 2 4 6 Time (hours) iigure 1. Boron concentrations in tumor and blood as a function of time. The blood curve is :;IC mean Xi for 8 patients infused (from 0-2 hrs) at the 250 mg BPA/kg dose level. All :::mor data have been arithmetically extrapolated to 250 mg BPAlkg. Multiple samples of tumor Acre obtained from each patient. Tumor data shown are the mean k sd. ;onventional photon inadiation, each of the high-LET dose components (physical dose in Cy) :S multiplied by an experimentally determined factor to correct for different degrees of biological c:fectiveness. The total effective, photon-equivalent BNCT dose is then expressed as the sum ofthe RBE-corrected components with a unit named Gy-Eq (Gray-Equivalent). The short ranges oi the two high-LET products of the '%(n,a)'Li reaction make the microdistribution of the boron relative to target cell nuclei of particular importance. Thus, there is a boron localization factor :o be considered in determining the biological effectiveness of the '%(n,a)'Li reaction. The dependence of the biological effect on variations in the microdistribution of different boron compounds, or the same boron compound in different tissues, makes the term RBE inappropriate :n describing the biologicai effectiveness of the '"B(n,a)'Li reaction. The term "CBE factor" i s  used and is defined as the product of the true, geometry-independent RBE for these high-LET panicles multiplied by a boron localization factor, which, will be different for each boron compound or for a given compound in different tissues. For BPA-basxi BNCT in tumor, the CBE-factor of 3.8 and the RBE ;or the high-LET beam components of 3.2 were determined from the results of in vivo/in virro clonogenic assays in the 9L gliosarcoma rat brain tumor model (3). For BPA-based E:JCT in norm: . brain, the CBE factor of 1.3 and the RBE for the high-!,ET beam components of 3.2 were dettrmined from dose-response studies of the irradiated rat spinai cord with an endpoint of imb paralysis within 7 months (4). DXSCLAIMER Portions of this document may be illegible in electronic image products. fmncres are produced from the best available original document. BNCT Clinical Trial: Study Design. The objectives of the Phase 1/11 clinical trial are: 1) To determine a safe starting dose for B N m  using epithermal neutrons: 2) To evaluate adverse effects of BNCT; and 3) TO evaluate the effectiveness of this starting BNCT dose Ievel in patients with GBM. Patients receive BPA at the time of craniotomy for a biodistribution study. Three to four weeks later, the patients receive another BPA infusion and are irradiated with the BMRR epithermal neutron beam. The starting dose to the normal brain was chosen with primary consideration given to safety and possible adverse effects. The administered dose of BPA-F is 250 mg BPA/kg delivered as a 2 hour i.v. infusion. BNCT is delivered in a single fraction for about 40-50 min (with a pause for blood sampling) using a single field. The peak and average radiation doses to the normal brain are determined from the masured boron concentration in the blood during the irradiation. The prescribed absolute peak dose in a 1 cm3 brain volume is 10.5 Gy-Eq. The peak dose rate will be kept below 27 cGy-Eq/min so as not to exceed that used ~ c h  p otons.in'whoie brain irradiation. The average dose to the whole brain volume will not exceed 7.5 Gy-Eq. The maximum dose to the scalp will not exceed 20 Gy-Eq. The deepest part of the mnmt enhancing tumor must be 5 6 cm from the scalp surface. The target dose to the deepest part of the contnst-enhancing region of tumor is 2 20 Gy-Eq. Clinical BNCT: Case Example Summary. The BNCT clinical trial is only recently underway and statistically valid clinical results are not yet available. Results from a representative case are presented to illustrate the approach. The thermal neutron fluence from the epithermal beam reaches a maximum at approximately 1 cm depth in the brain, or about 3 cm depth from the scalp surface. The average '9 concentration in the blood during the irradiation was 15 pg ''%/g. To reach the prescribed dose of 10.5 Gy-Eq to the peak dose volume (1 cm3 volume at 3 cm depth from the scalp surface) required a peak thermal neutron fluence of 3.3 x lo1* n/cm2. The total irradiation time was 88 MW-min (or 44 min at 2 MW BMRR power). The absolute peak physical dose (I cm3 voxel) to normal brain was 7.9 Gy (3.47 Cy from the '%(n,cr)'Li reaction, 3.66 Gy gamma, 0.40 Gy from the l 'N(r~,p)~~C reaction, and 0.33 Gy from fast neutrons). Using the RBE and CBE factor vaiues listed above, the peak physical dose of 7.9 Gy corresponds to the 10.5 Gy-Eq prescribed maximum brain dose. The estimation of tumor dose depends on the value assumed for the tumor/blood boron concentration ratio. Correlation of the measured boron concentrations with the degree of cellularity in histological sections taken from the same tumor samples indicate that non-necrotic, viable glioblastoma accumulates 3 times more BPA than is present in the blood. Thus, for 45 pg %/g in tumor, and 88 MW-min irradiation time, the peak dose (1 cm3 volume) was 47.8 Gy- E q .  The minimum dose to the tumor volume was = 50% of the absolute peak dose. Examination of the normal brain isodose contours on MRI images at diff5rent levels in the brain a3:owed an estimation of the dose to other vital structures. Expressed as a percentage of the absolute peak dose, 10.5 Gy-Eq, tnese deses were: ipsilateral basal ganglia, 65%; hypothalamus, 50%; cerebral midline, 25%; optic chiasm, I 20%; retina, 5 10%. The dosdvolurne relationships for the normal Drain and the tumor are shown for this case example in Figure 2. The average dose to the entire brain volun-e was 2.8 Gy-Eq (ipsiiateral hemisphere, 4.4 Gy-Eq; contralateral hemisphere, 1.2 Gy-Ti). DISCLAIMER This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsi- bility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Refer- ence herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recom- mendation, or favoring by the United States Government or any agency thereof. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof. Surriinary: Ten patients have received BPA-based BNCT under the protocol outlined above. rhere have been no unexpected acute effects in the normal brain. Several patients have been iollowed for greater than 4 months with no observed effects on normal brain. Scalp showed riiild erythema in a few patients at = two weeks post BNCT. Epilation was observed in all ~ascs within the 8 cm diameter treatment field. Tumor recurrence has been observed in several patlcnts after intervals of 7.5, 6 and 4 months, respectively. Correlation of the site of the recurrence with the original treatment plan is in progress. It appears that tumor recurrence is ,if depths where the tumor dose falls below 20 Gy-Eq. Plans for dose escalation are in progress. This research was supported in part by U.S. DOE under Contract DE-AC02-76CH00016. I ---r----l 0.8 E I Tumor 4 - c a, W E n i Normal Brain L. 0.0 I I I 0 10 20 30 40 50 .- U Dose (Gy-Eq) Figure 2. Dose-voiume relationships for the tumor and the normal brain. The average blood- boron concentration during BNCT was 15 pg 'OB/g. Based on correlations of the data from the biodistribution study with cellularity in histological sections, the average boron concentration in the tumor was assumed to be 3 x that in the blood, or 45 p g  %/g. REFERENCES 1. 2 .  3. 4. K. Yoshino, A. Suzuki, Y. Mon et ai., Srruhlenther. Oncol. 165, 127-129 (1989). H. Fukuda, J. Hiratsuka, C. Honda et al., Radiat. Res. 138, 435-442 (1994). J.A. Coderre, M.S. Makar, P.L. Micca et al., Inr. J .  Radiat. 3ncol. Bioi. Phys. 27, G.M. Moms, J.A. Codei're. J.W. Hopewell et ai., Radinrher. Oncol. 32, 249-255 (1994). 1121-1129 (1993). 

Early clinical experience of boron neutron capture therapy for glioblastoma multiforme

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Early clinical experience of boron neutron capture therapy for glioblastoma multiforme

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